The Disulfide Bonds within BST-2 Enhance Tensile Strength during Viral Tethering

Biochemistry. 2016 Feb 16;55(6):940-7. doi: 10.1021/acs.biochem.5b01362. Epub 2016 Feb 4.

Abstract

Human BST-2/tetherin is a host factor that inhibits the release of enveloped viruses, including HIV-1, HIV-2, and SIV, from the cell surface by tethering viruses to the host cell membrane. BST-2 has an α-helical ectodomain that forms disulfide-linked dimers between two monomers forming a coiled coil. The ectodomain contains three cysteine residues that can participate in disulfide bond formation and are critical for viral tethering. The role of the disulfides in viral tethering is unknown but proposed to be for maintaining the dimer. We explored the role of the disulfides in the structure of BST-2 using experimental, biophysical methods. To understand the role of the disulfides in viral tethering, we used a new approach in viral tethering, steered molecular dynamics. We find that the disulfides coordinate the unfolding of the BST-2 monomers, which adds tensile strength to the coiled coil. Structural differences between oxidized and reduced BST-2 are apparent during unfolding, showing the monomers slide past each other in the absence of the disulfides. We found no evidence to support dissociation of the dimer upon reduction of the disulfide bonds. Moreover, the structure of BST-2 in the absence of the disulfides is similar to that of the oxidized form of BST-2, supporting previous X-ray crystallography and cellular work that showed the disulfides are not required for expression of BST-2. These data provide new insights into viral tethering by using novel techniques in the analysis of BST-2 to give amino acid level insight into functions of BST-2.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antigens, CD / chemistry
  • Antigens, CD / metabolism*
  • Disulfides / chemistry
  • Disulfides / metabolism*
  • GPI-Linked Proteins / chemistry
  • GPI-Linked Proteins / metabolism
  • HIV-1 / metabolism
  • HeLa Cells
  • Humans
  • Scattering, Small Angle
  • Tensile Strength / physiology*
  • Viral Envelope Proteins / metabolism*
  • Virus Release / physiology*

Substances

  • Antigens, CD
  • BST2 protein, human
  • Disulfides
  • GPI-Linked Proteins
  • Viral Envelope Proteins